The goal of this proposal is to understand how a successful vaccine induces long-term immunological memory in humans. To achieve this goal we propose to conduct a detailed cellular and molecular characterization of human immune responses induced by the yellow fever virus (YFV) vaccine. This is one of our most efficacious vaccines and induces long-term immunity that lasts for decades. Also, since YFV-17D is a live attenuated vaccine and most of the U.S. population is not exposed to YFV, this provides a unique opportunity to analyze antiviral responses in humans during the course of a primary infection and then to monitor the generation and maintenance of immune memory after resolution of the infection. One of the potential benefits of understanding how a successful vaccine induces long-term memory is that this knowledge can be applied to improving other less effective vaccines. Such a comparison could define the signatures of a "good" versus "bad" vaccine and provide a rational basis for improving vaccine efficacy. To address this issue, we will examine human immune responses induced by the anthrax vaccine. We have chosen to study the anthrax vaccine because of the obvious importance of anthrax in biodefense-related research and also because there is clearly a need for a better anthrax vaccine. However, prior to designing strategies for improving the anthrax vaccine, it is first essential to better characterize the magnitude and quality of the immune responses induced in humans by the currently licensed anthrax vaccine. The specific aims of this proposal are as follows: 1. To determine if there is an early global sensitization of naIve T and B cells after immunization and to see if this correlates with the magnitude and duration of the adaptive immune response. 2. To characterize the primary and memory T cell responses to YFV and anthrax vaccine. 3. To define the molecular and functional profile of memory T cell differentiation in vivo following an acute viral infection and to examine how the strength and duration of T cell stimulation effects memory differentiation. 4. To examine bystander effects on memory T cells during viral infection in humans. 5. To understand the mechanisms of long-term serological memory and to define the gene expression profiles of memory B cells.